64Cu uPAR Conjugates for Higher Tumor Binding and Retention
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Solution Overview
Problem
Current radionuclide labelled peptide conjugates for uPAR targeting have poor tumor binding and retention, limiting their effectiveness in targeted radiotherapy for uPAR expressing cancers.
Innovation Solution
Development of 64Cu labelled uPAR binding conjugates comprising a uPAR binding moiety, a chelating agent, and the radionuclide 64Cu, which provides high tumor binding and good retention, allowing therapeutic efficacy at doses below theoretical limits.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If radionuclide labelled peptide conjugates are used for uPAR targeting, then targeted radiotherapy can be delivered, but tumor binding and retention are poor
Solution Approach 1:
The patent modifies the peptide conjugate structure by changing the linker parameters and chelating agent configuration to improve tumor binding and retention. Specifically, the use of modified peptide sequences and optimized linker lengths alters the pharmacokinetic parameters to achieve better tumor accumulation and retention characteristics.
Solution Approach 2:
The invention creates a composite structure combining the uPAR-targeting peptide with a chelating agent and radionuclide in a specific configuration. This composite conjugate design integrates multiple functional components (targeting moiety, linker, chelator, radionuclide) to achieve both high tumor binding and stable radionuclide retention simultaneously.
2Productivity
If higher radionuclide doses are administered to achieve therapeutic effect, then tumor treatment efficacy improves, but side effects increase
Solution Approach 1:
The patent achieves localized delivery of high radionuclide activity specifically to tumor tissue through the uPAR-targeting peptide. This local quality approach concentrates the therapeutic effect at the tumor site while minimizing systemic exposure, allowing high doses to be delivered to the tumor without proportionally increasing side effects to healthy tissues.
Solution Approach 2:
The invention utilizes the short half-life of the radionuclide (e.g., 64Cu with 12.7 hours or 67Cu with 2.6 days) to deliver therapeutic effect quickly before significant decay occurs. This short-living approach allows high initial activity to be administered for immediate therapeutic effect while the rapid decay limits prolonged radiation exposure and cumulative side effects.
3Measurement precision
If 64Cu is used for imaging purposes, then diagnostic accuracy is achieved, but therapeutic efficacy is insufficient
Solution Approach 1:
The patent employs radionuclides like 64Cu and 67Cu that can serve dual purposes: 64Cu for PET imaging (diagnostic) and both 64Cu/67Cu for therapy (therapeutic). The same targeting conjugate structure is used with different radionuclides to achieve either diagnostic or therapeutic goals, or both in a theranostic approach, making the system universally applicable for both imaging and treatment.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The 64Cu labelled conjugates offer a wider therapeutic window with an optimal balance of therapeutic effect and side effects, achieving significant tumor treatment at reduced doses compared to conventional radionuclides.
Implementation Method 1
The radionuclide 64Cu is a well-known positron emitting radionuclide
Implementation Method 2
where the positron annihilates with an electron, producing two gamma photons that are detected simultaneously
Implementation Method 3
64Cu also decays by both beta minus particles and gamma radiation
Implementation Method 4
a chelating agent suitable for binding radiometals
Data Source
Figure 1A~1B
Figure 1C~2A
Figure 2B~2C
AI summary
The present invention provides Therapeutic application of 64Cu labelled uPAR binding conjugates, such as 64Cu-DOTA-AE105, for site-specific targeting of the Urokinase Plasminogen Activator Receptor (uPAR) in treatment of cancer diseases associated with high uPAR expression.